The major goal of the study was the elucidation of the role of prostaglandin E2 (PGE2) receptors (EP) in mouse skin tumorigenesis. Epidemiological studies in humans have confirmed an important role of PGs, including PGE2, in a variety of cancers including skin cancer. PGE2 produced via the cyclooxygenases (COX-1/COX-2) act on four different cell surface receptors (EP 1, -2, -3, -4), which belong to the family of GPCRs. We found that the EP2 and EP4 receptors were over-expressed in papillomas, but only the EP2, and not EP4, receptor was involved in tumor formation. EP2 was involved in the activation of several signaling cascades commonly associated with a variety of cancers. In summary, we show that Ras expression and activation and EGFR activation are regulated by EP2 and that EP2 contributes to papilloma development by activating proliferation and pro-survival pathways.